Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
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  • C07C255/00—Carboxylic acid nitriles
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/57—Nitriles
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• U.S. Patent No. 4,644,010 further discloses analgesic ⁇ -oxo- ⁇ -phenylcarbamoyl- ⁇ -pyrrolylpropionitriles, wherein the pyrrole nitrogen atom is unsubstituted.
• the related benzoylcyanoacetanilides and the corresponding o- and p-toluidides and p-anisidides have been described already by Dains and Griffin, J. Am. Chem. Soc. 35, 959-(1913), but without mentioning any physiological property.
• the present invention is concerned with ⁇ -(substituted carbamoyl)-,8-aryl- and heteroaryl- ⁇ -oxopropionitriles of formula enol ethers thereof and salts thereof, as well as with pharmaceutical preparations containing same and methods of preparing and using these compounds.
• Said compounds represent novel antiinflammatory and antirheumatic agents. Their property to interfere with both the cyclooxygenase and lipoxygenase pathway of the arachidonic fatty acid bioconversion to inflammatory mediators make them valuable therapeutics. These properties render the mentioned substituted carbamoyl-,8-oxopropionitriles useful for the treatment of arthritic and rheumatic diseases and other inflammatory conditions in mammals.
• the invention relates to compounds of formula wherein A is selected from the group consisting of five- and six-membered unsubstituted or substituted aromatic heterocyclyl with the exception of pyrrolyl, five- and six-membered aromatic heterocyclyl-vinyl, and unsubstituted and substituted phenyl, and wherein B is unsubstituted or substituted phenyl, pyridyl or thiazolyl, with the proviso that when A is unsubstituted phenyl B does not represent unsubstituted phenyl, methylphenyl or methoxyphenyl, further to enol tautomers, lower alkyl enol ethers and salts thereof.
• lower referred to above and hereinafter in connection with organic radicals or compounds, respectively, defines such with up to and including 7, preferably up to and including 4, and advantageously one or two carbon atoms.
• a lower alkyl group preferably contains 1-4 carbon atoms and represents, for example, ethyl, propyl, butyl or advantageously methyl.
• a lower alkoxy group preferably contains 1-4 carbon atoms and represents, for example, ethoxy, propoxy, isopropoxy or advantageously methoxy.
• Halogen preferably represents chloro or fluoro but may also be bromo or iodo.
• a five- or six-membered aromatic heterocyclyl residue of the invention comprises, for example, one oxygen atom, one sulfur atom, one, two, three or four nitrogen atoms, or both one nitrogen atom and one oxygen or sulfur atom.
• a heterocyclyl residue is, for example, 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-imidazolyl, 3-, 4- or 5-pyrazolyl, 1,2,4-triazolyl, tetrazolyl, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 2-, 3- or 4-pyridyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl, or 3- or 4-pyridazinyl.
• heterocycles may be substituted, for example at carbon atoms by one or more residues selected from lower alkyl, for example methyl, phenyl-lower alkyl, for example benzyl, phenyl, heterocyclyl, for example 2-or 3-furyl or 2- or 3-thienyl, and halogen, for example chloro or bromo, and at a nitrogen atom by lower alkyl, for example methyl, or phenyl-lower alkyl, for example benzyl.
• lower alkyl for example methyl, phenyl-lower alkyl, for example benzyl, phenyl, heterocyclyl, for example 2-or 3-furyl or 2- or 3-thienyl, and halogen, for example chloro or bromo
• Examples for such substituted heterocyclyl residues are 5-methyl-2-furyl, 4- or 5-phenyl-2-furyl, 5-chloro-2-furyl, 5-bromo-2-furyl, 5-methyl-2-thienyl, 3,4-dimethyl-2-thienyl, 4- or 5-phenyl-2-thienyl, 5-(2-thienyl)-2-thienyl, 1-methyl-2- or 5-imidazolyl, 1-benzyl-2- or 5-imidazolyl, 1,3-dimethyl-5-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 5-methyl-3-isoxazolyl, 2-methyl- or phenyl-4-thiazolyl, 4-methyl- or phenyl-2-thiazolyl, 2,4-dimethyl-5-thiazolyl; 4-, 5- or 6-methyl-2-pyridyl, or 2,6-dimethyl-4-pyridyl.
• a five- or six-membered aromatic heterocyclyl-vinyl group is preferably 2-substituted vinyl bearing one of the mentioned heterocyclyl residues, for example 2-(2-furyl)-vinyl, 2-(2-thienyl)vinyl, 2-(2-pyridyl)vinyl, and also 2-(2-pyrrolyl)vinyl or 2-(1-methyl-2-pyrrolyl)vinyl.
• Substituted phenyl is a phenyl group bearing one, two, three, four or five, particularly one or two, substituents, for example selected from the group consisting of lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for example methoxy, halogen, for example chloro or fluoro, or trifluoromethyl.
• Such substituted phenyl is, for example, o-, m- or p-tolyl, 3,4-xylyl, 2,6-xylyl, p-biphenylyl, p-hydroxyphenyl, o- or p-methoxyphenyl, 3,4-dimethoxyphenyl, o-, m- or p-chlorophenyl, 2,4- or 3,4-dichiorophenyi, 3-chloro-4-methylphenyl, m- or p-fluorophenyl, 2,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, m-or p-trifluoromethylphenyl, or 4-chloro-3-trifluoromethylphenyl.
• Enol tautomers of the compounds of formula I are in equilibrium with said compounds of formula I and may be represented by following formulae wherein A and B have the meanings as previously defined for compounds of formula I.
• There are also other enol tautomers to be considered being in equilibrium with the basic structure shown in formula I for example enol tautomers involving the carbamoyl carbonyl function, as in formula and di-enolic tautomers of formula
• Lower alkyl enol ethers of the invention are those wherein the hydrogen atom of an enolic hydroxy group in one of the mentioned enol tautomers is replaced by lower alkyl, for example ethyl or preferably methyl.
• an enol ether of the invention is a compound of above formula la, wherein the hydrogen atom of the hydroxy group is replaced by lower alkyl, for example methyl.
• the compounds of formula I have acidic properties and readily form salts derived from enolic tautomers of formula la, Ic or Id with suitable inorganic or organic bases.
• Salts of compounds of formula I are especially pharmaceutically acceptable, non-toxic salts, for example alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example magnesium or calcium salts, zinc salts, ammonium salts, and in particular salts with organic amines, such as optionally hydroxy-substituted mono-, di- or trialkylamines, for example with 2-hydroxyethylamine, tris-(hydroxymethyl)methylamine, diethylamine, di-(2-hydroxyethyl)amine, triethylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine or N-methyl-D-glucamine, with cyclic amines, for example pyrrolidine or morpholine, or with corresponding
• Acid addition salts preferably are pharmaceutically acceptable, non-toxic salts, for example salts with strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid; with aliphatic or aromatic carboxylic acids, e.g.
• methanesulfonic ethanesulfonic, hydroxyethanesulfonic, benzeriesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid.
• the compounds of the invention exhibit valuable pharmacological properties, primarily antiinflammatory, analgesic (antinociceptive), antirheumatic, and antiarthritic activity. These can be demonstrated by in vitro or in vivo tests, using for the latter advantageously mammals, such as rats, mice, guinea pigs or dogs, as test objects.
• the compounds of the invention can be adminstered to the animals either enterally, preferably orally, parenterally, e.g. subcutaneously or intravenously, or topically, for example, in the form of aqueous or oily solutions or starchy suspensions.
• the applied dosage may range between about 0.1 and 100 mg/kg/day, preferably between about 1 and 50 mg/kg/day, advantageously between about 5 and 25 mg/kg/day.
• the tests chosen are among the classical assay methods for said activities, such as the carrageenin paw-edema, or adjuvant arthritis tests in rats, the canine synovitis or ultraviolet erythema assays, or more recent tests, such as neutral protease inhibition, inhibition of leukocyte chemotaxis, decrease of neutrophil adherence, inhibition of prostaglandin synthetase or cyclooxygenase, inhibition of 5- lipoxygenase, the phenylquinone writhing test in mice, or inhibition of cartilage matrix degradation.
• the tests chosen are among the classical assay methods for said activities, such as the carrageenin paw-edema, or adjuvant arthritis tests in rats, the canine synovitis or ultraviolet erythema assays, or more recent tests, such as neutral protease inhibition, inhibition of leukocyte chemotaxis, decrease of neutrophil adherence, inhibition of prostaglandin synthetase or cyclooxygenase,
• the carrageenin paw-edema assay for antiinflammatory activity is carried out in rats as follows:
• the established adjuvant arthritis test for antiarthritic activity is performed essentially as described in Proc. Soc. Biol. Med. 137, 506 (1971).
• Several compounds of the invention are effective in the established adjuvant arthritis test in the rat affording 30% to 70% protection when administered at a dose ranging from 10 to 25 mg/kg p.o.
• the compounds of the invention demonstrate dual 5-lipoxygenase/cyclooxygenase inhibitory activity.
• Most non-steroidal antiinflammatory drugs (NSAIDs) including some of the previously disclosed 6-oxo-a-phenylcarbamoyl-,6-pyrrolylpropionitriles are known to block selectively the cyclooxygenase pathway thereby prohibiting or at least slowing down the formation of prostaglandins, thromboxanes and prostacyclins from arachidonic acid.
• This inhibitory action on cyclooxygenase produces the desired antiinflammatory effect but at the same time may increase the formation of leukotrienes by the alternative arachidonic acid metabolism in the lipoxygenase pathway.
• Leukotrienes are a group of mediators with potent leukocyte- chemoattractant, smooth muscle-constricting and vascular permeability-enhancing properties. Leukotrienes have been implicated in the pathogenesis of a variety of vascular and pulmonary disorders involving leukocyte and smooth muscle activation.
• Prostaglandin synthetase inhibition is determined essentially by assaying in vitro PGE 2 formation from arachidonate as described by Takeguchi et al., Biochemistry 10, 2372 (1971) and by Tomlinson et al., Biochem. Biophys. Res. Commun. 46, 552 (1972). Cyclooxygenase inhibition may also be measured by the radiometric assay described in Ku ⁇ ral., Biochem. Pharmacol. 24, 641 (1974).
• 5-Lipoxygenase inhibition is determined e.g. by measuring the percent inhibition of the synthesis of 5-HETE [(5S)-5-hydroxy-6,8,11,14-eicosatetraenoic acid] and leukotriene B 4 (LTB 4 , 5,12-dihydroxy-6,8,10,14- eicosatetraenoic acid) in ionophore A-23187-stimulated guinea pig polymorphonuclear leukocytes, essentially according to the procedure described by Borgeat and Samuelsson, Proc. Natl. Acad. Sci. USA 76, 2148 (1979), using 14 C-arachidonic acid.
• IC 50 values are determined graphically as the concentration of test compound at which the synthesis of 5-HETE and L TB 4 -like products is reduced to 50% of their respective control values.
• Compounds of the invention are usually highly effective inhibitors of prostaglandin synthetase as determined in the bull seminal vesicle microsome enzyme assay, with 50% inhibition concentrations (IC so ) in the range of 1 to 100 aM. At the same time these compounds show ICso in the range of 1 to 100 aM for 5-lipoxygenase inhibition as measured in vitro in A-23187-stimulated guinea pig polymorphonuclear leukocytes.
• the compounds of the invention reduce neutrophil activation, a property that is indicative of antiarthritic activity, e.g. in the treatment of rheumatoid arthritis.
• Inhibition of leukocyte chemotaxis may be measured as described in Ann. N.Y. Acad. Sci. 256, 177 (1975).
• the inhibition of the chemotactic activation of neutrophils is also determined in vitro, e.g. by measuring the inhibition of the binding of f-MLP (formyl-methionyl-leucyl-phenyl-alanine) to human neutrophils in vitro as follows: Human neutrophils are isolated by a modification of the procedure of Ferrante and Thong, J. Immunol. Methods 24, 389 (1978). Red cells remaining in the neutrophil preparation are lysed by separate treatments with 0.83%NH 4 Cl and 0.1 M tris-HCI, pH 7.5.
• Neutrophils are incubated in Hanks' buffer at 0 C for 60 minutes with 15 nM 3 H-f-MLP and test compound. Aliquots of the incubates are filtered and total 3 H-f-MLP bound is measured. Non-specific binding in the presence of excess non-radioactive f-MLP is subtracted, and percent inhibition of binding by the test drug is calculated.
• IC 50 of compounds of the invention inhibiting binding of f-MLP to human neutrophils are in the range of 1 to 20 ⁇ M.
• mice The phenyl-p-benzoquinone-induced writhing test for analgesic activity, described in J. Pharmacol. Exp. Thera. 125, 237 (1959) is performed in mice as follows: Mice previously fasted overnight are treated orally with the test compound dissolved in 0.75% methylcellulose at doses of 1 to 50 mg/kg, or with the vehicle alone, 55 minutes before the induction of the writhing syndrome by i.p. injection of 0.25 ml of a suspension of phenyl-p-benzoquinone (0.03%) in tragacanth (0.4%). Starting 5 minutes, thereafter, the number of writhing movements provoked by the irritant are counted over an observation period of 10 minutes.
• the analgesic (antinociceptive) EDso of the test compound is the dose which reduces the mean frequency of writhing movements by 50% in comparison to the controls.
• the compounds of the invention are also active in the cartilage-synovium co-culture model of cartilage matrix degradation, indicative of their effectiveness in osteoarthritis.
• the screen is carried out as follows: The proteoglycan matrix of bovine nasal septum cartilage is labeled in vitro by incorporation of 35 S into glycosaminoglycan. Cartilage slices are incubated overnight in a sulfate-free medium containing 35 S-sodium sulfate. 35 S-Labeled cartilage slices are co-cultured with normal synovium explants in multiwell tissue culture plates. After 4 days incubation a 100 ⁇ l aliquot of medium is counted. Cartilage slices are hydrolyzed and a 100 ⁇ l aliquot of cartilage hydrolysate is counted. The percent 35 S released into the medium is determined and the percent of inhibition of matrix degradation is calculated.
• the aforementioned advantageous properties render the compounds of the invention useful as antiinflammatory, analgesic and antiarthritic agents especially for the treatment and amelioration of e.g. pain and inflammatory disorders, such as rheumatoid arthritis and osteoarthritis in mammals, including man.
• A is selected from the group consisting of five membered aromatic heterocyclyl comprising one oxygen atom, one sulfur atom, or two heteroatoms wherein one is nitrogen and the other one is nitrogen, oxygen or sulfur, and wherein the aromatic heterocycle is unsubstituted or substituted at carbon atoms by one, two or three residues selected from lower alkyl, phenyl, furyl, thienyl and halogen, and at a nitrogen atom by lower alkyl; six-membered aromatic heterocyclyl comprising one or two nitrogen atoms, unsubstituted or substituted at carbon atoms by lower alkyl or phenyl; furylvinyl; thienylvinyl; and phenyl substituted by one or two residues selected from lower alkyl, phenyl, hydroxy, lower alkoxy, halogen and trifluoromethyl; and
• B is selected from the group consisting of phenyl; phenyl substituted by one or two residues selected from lower alkyl, phenyl, hydroxy, lower alkoxy, halogen and trifluoromethyl; pyridyl; and thiazolyl.
• Equally useful are compounds of formula I, enol tautomers, lower alkyl enol ethers and salts thereof, wherein A is phenyl and B is phenyl substituted by one or two residues selected from halogen and trifluoromethyl.
• A is 2-or 4-imidazolyl, 1-methyl-2- or 5-imidazolyl, 3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 3- or 5-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methyl-5-isoxazolyl, 2-, 4- or 5-thiazolyl, 2-methyl- or phenyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, or 2-, 3- or 4-pyridyl, and B is phenyl unsubstituted or substituted by one or two residues selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro, chloro and trifluoromethyl.
• compounds of formula I, enol tautomers thereof and salts thereof wherein A is phenyl substituted by C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro or chloro, and B is phenyl unsubstituted or substituted by one or two residues selected from C l -C 4 .-alkyl, C 1 -C 4 -alkoxy, fluoro, chloro and trifluoromethyl, or wherein A is phenyl and B is phenyl substituted by one or two residues selected from fluoro and chloro.
• A is 2-furyl or 2-thienyl and B is phenyl, chlorophenyl, fluorophenyl, trifluoromethylphenyl, dichlorophenyl, difluorophenyl, or chlorofluorophenyl.
• the present invention also relates to processes for the manufacture of compounds of formula I and salts thereof. These can be prepared according to methods known per se to those skilled in the art, for
• the condensation according to process (a) of the substituted ⁇ -oxopropionitrile of formula II with an isocyanate of formula III may be carried out under a variety of reaction conditions, without a solvent or in the presence of an unpolar or a non-protic, inert polar solvent in a temperature range between 0°C to 200 C, optionally in the presence of an inorganic or organic base.
• Useful solvents are, for example, hydrocarbon solvents, e.g. benzene, toluene, xylene, or cyclohexane, ethers, e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, or dioxane, esters, e.g. ethyl acetate, amides, e.g. dimethyl formamide or N-methylpyrrolidone, nitriles, e.g. acetonitrile, or other dipolar aprotic solvents, e.g. dimethylsulfoxide.
• hydrocarbon solvents e.g. benzene, toluene, xylene, or cyclohexane
• ethers e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, or dioxane
• esters e.g. ethyl
• the reaction is run in the presence of an inorganic base, for example sodium or potassium hydride, sodium or potassium carbonate or the like, or in the presence of an organic base, particularly a tertiary amine, e.g. triethylamine, tributylamine or dimethylaniline, or a pyridine base, e.g. pyridine.
• an inorganic or organic base lowers the reaction temperature considerably, for example to a range of 0°C to about 50°C, preferably around room temperature. Otherwise temperatures between 80 C and 150' C are contemplated, for example at the boiling temperature of the solvent used.
• Salts of substituted ⁇ -oxopropionitriles of formula II used in process (a) are particularly alkali metal salts, for example sodium or potassium salts, or earth alkali metal salts, for example magnesium salts, or else ammonium salts. If the mentioned salts are used in the process, the preferred temperature range is 0°C to about 50 °C without added extra base. Polar solvents such as dimethyl formamide or dimethylsulfoxide are preferred when using salts.
• Process (a) is preferably performed in the following way:
• the substituted ⁇ -oxopropionitrile of formula II is treated with a slight molar excess of an anhydrous tri-lower alkylamine, preferably triethylamine, in one of the above-mentioned solvents, and then a molar equivalent of the appropriate isocyanate of formula III is added, or a solution thereof in the mentioned solvents.
• the reaction mixture is reduced in volume by evaporation without excessive warming.
• the residue is treated with an excess of dilute aqueous acid, e.g.
• p-oxopropionitriles of formula 11 are obtained by condensation of acetonitrile with corresponding carboxylic esters in the presence of e.g. sodium ethoxide, sodium methoxide or sodium hydride, in polar solvents such as the corresponding alcohol, dimethoxyethane or dimethyl formamide, or mixtures thereof with toluene or other hydrocarbon solvents.
• polar solvents such as the corresponding alcohol, dimethoxyethane or dimethyl formamide, or mixtures thereof with toluene or other hydrocarbon solvents.
• ⁇ -oxopropionitriles of formula II may be formed by condensation of ethyl formate with the corresponding methyl ketone, cyclocondensation of the obtained S-substituted ⁇ -oxopropionaldehyde to an isoxazole, and cleavage of the isoxazole with sodium hydroxide solution.
• S-oxopropionitriles of formula II include thermolytic decarboxylative cleavage of 5-substituted isoxazole-3-carboxylic acids, substitution of chlorine by cyanide in chloromethylketones, or mixed condensation of an (aryl- or heteroaryl-)nitrile with acetonitrile followed by acid hydrolysis of the obtained ⁇ -substituted ⁇ -aminoacrylonitrile.
• Process (b) involving reaction of a carboxylic acid of formula IV or a functional derivative thereof with a primary amine of formula V is carried out in a manner well-known.
• Suitable functional derivatives are carboxylic acid chlorides, anhydrides, for example symmetric anhydrides or mixed anhydrides with formic acid, acetic acid or preferably carbonic acid semi-esters, or esters, for example lower alkyl esters, preferably methyl or ethyl esters.
• Further suitable functional derivatives are those disclosed in U.S. Pat. No. 4,727,060 for the formation of an amide bond, for example reactive esters or reactive cyclic amides.
• a carboxylic acid chloride or anhydride is used as the functional derivative of a compound of formula IV
• the condensation is carried out with an excess of the amine of formula V or with an equivalent amount of said amine and an equivalent or excess amount of another, non-reactive base, for example a tertiary amine, e.g. a tri-lower alkylamine such as triethylamine, or pyridine, in order to neutralize the generated acid.
• the reaction is carried out without solvent in an excess of the amine or in an unpolar or an aprotic polar solvent such as those mentioned under process (a), for example in an ether, e.g.
• diethyl ether diethyl ether, tetrahydrofuran or dioxane, or in acetonitrile or a like dipolar aprotic solvent.
• Protic solvents for example alcohols, e.g. ethanol or isopropanol, may also be used, but are less desirable.
• the condensation is performed at temperatures between -30 C and +80°C depending on the reactivity of the acid derivative used, preferably between 0 C and room temperature.
• a carboxylic ester is used as the functional derivative of a compound of formula IV
• the condensation is carried out at a higher temperature, for example between 80 C and 200 C.
• a high-boiling hydrocarbon solvent such as benzene, toluene or xylene, and the reaction is conducted at the boiling point of said solvent in order to remove the alkanol generated in the condensation of the ester with the amine.
• Starting materials of formula IV are known. If they are novel, they are prepared by methods known in the art, for example by acylation of a sodium or potassium salt of a cyanoacetic ester with a carboxylic acid chloride or anhydride, e.g. a mixed anhydride with a carbonic acid semi-ester, in the presence of an inert, unpolar or aprotic dipolar solvent.
• a sodium salt of ethyl cyanoacetate obtainable from ethyl cyanoacetate and sodium hydride is acylated with a suitable acid chloride or mixed anhydride with carbonic acid mono-ethyl ester in dimethoxyethane or a like polar solvent.
• free acids of formula IV may be obtained by carboxylation of corresponding ⁇ -oxopropionitriles with magnesium dimethyl carbonate, prepared by carbonation of magnesium methoxide in dimethyl formamide.
• Ester derivatives of compounds of formula IV are also available by reaction of ⁇ -substituted ⁇ -oxopropionitriles with chloroformates in the presence of base.
• the condensation reaction of process (c) is carried out under conditions generally known for acylations of ⁇ -Ketonitriles or ⁇ -ketoesters.
• Useful functional derivatives of a carboxylic acid of formula VI are the corresponding acid chlorides and acid anhydrides, for example symmetrical anhydrides or mixed anhydrides with e.g. formic acid, acetic acid or carbonic acid lower alkyl semi-esters, activated esters, for example succinimido, phthalimido, 4-nitrophenyl or vinyl esters, or activated amides, for example imidazolides or 3,5-dimethylpyrazolides.
• the reaction is carried out in one of the solvents mentioned under process (a), preferably in a polar ether, for example in dimethoxyethane, tetrahydrofuran or dioxane, in an inert dipolar aprotic solvent, for example in dimethyl formamide, N-methylpyrrolidone or dimethylsulfo xide, or in mixtures of said solvents with each other or with a hydrocarbon solvent, for example with toluene, at temperatures between 0 C and 100 C, preferably between 20 C and 50° C, for example around room temperature.
• a polar ether for example in dimethoxyethane, tetrahydrofuran or dioxane
• an inert dipolar aprotic solvent for example in dimethyl formamide, N-methylpyrrolidone or dimethylsulfo xide
• a hydrocarbon solvent for example with toluene
• the acylation reaction of process (c) may also be carried out using the mentioned acid chloride and the ⁇ -ketonitrile of formula VII in the presence of an activating base, for example 4-dimethylaminopyridine, or using the free carboxylic acid in the presence of a condensing agent, for example diethyl phosphorocyanidate, and in the presence of a base, for example triethylamine, in the mentioned preferred solvents and at the temperatures given.
• an activating base for example 4-dimethylaminopyridine
• a condensing agent for example diethyl phosphorocyanidate
• a base for example triethylamine
• Starting materials of formula VII are either known or are prepared by methods known in the art. For example they are obtained by reaction of cyanoacetic acid or a functional derivative thereof with the corresponding amine of formula V under the conditions mentioned under process (b) for the formation of an amide.
• the hydrolysis of an isoxazole in process (d) is carried out using strong inorganic or organic bases, for example aqueous alkali metal hydroxides, e.g. lithium, sodium or potassium hydroxide, or quaternary ammonium hydroxides, e.g. benzyltrimethylammonium hydroxide.
• strong inorganic or organic bases for example aqueous alkali metal hydroxides, e.g. lithium, sodium or potassium hydroxide, or quaternary ammonium hydroxides, e.g. benzyltrimethylammonium hydroxide.
• the isoxazoles of formula VIII are cleaved in the mentioned aqueous strong bases at temperatures between room temperature and 100°C, preferably between 50 °C and 80 °C.
• An organic co-solvent may be added to the reaction mixture to enhance solubility and thereby lowering the required reaction temperature, for example a lower alkanol, e.g. methanol or ethanol, or
• the isoxazole starting materials of formula VIII are formed by reactions known in the art, for example by cyclocondensation of the corresponding a-formyl- or ⁇ -aminomethylene- ⁇ -oxopropionamides with hydroxylamine hydrochloride in aqueous methanol.
• the required tricarbonyl compounds or their equivalents are available by an acylation reaction similar to the one described in process (c), for example by formylation of the corresponding ⁇ -substituted ⁇ -oxopropionamide with a suitable formic acid ester, or by equivalent aminomethylenation using, for example, a dimethyl formamide acetal, N-phenylformamidine, or a mixture of a primary amine and a formic acid orthoester.
• the hydrolysis of an isoxazole in process (d) can also be performed under the specified conditions with concomitant ester hydrolysis and decarboxylation starting with a corresponding isoxazole-3-carboxylic ester, for example a methyl or ethyl ester.
• the isoxazole-3-carboxylic ester starting materials are formed by cyclocondensation of the corresponding a-methoxalyi- or ⁇ -ethoxalyl- ⁇ -oxopropionamides with hydroxylamine hydrochloride. These methoxalyl or ethoxalyl derivatives are available by ester condensation of methyl or ethyl oxalate and corresponding p-substituted ⁇ -oxopropionamides.
• Cleaving a conventional protecting group from a compound of formula IX in process (e) is carried out by methods well-known in the art, depending on the type of protecting group present.
• Conventional protecting groups and corresponding deprotection reactions are described, for example in standard works, such as in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in “The Peptides”, volume 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981, and in “Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol. 15/1, Georg Thieme Verlag, Stuttgart 1974.
• benzyl, diphenylmethyl, trityl, benzyloxycarbonyl and substituted derivatives of said protecting groups are cleaved by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst.
• a suitable hydrogenation catalyst such as a palladium catalyst.
• 2-Halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, or aroylmethoxycarbonyl protecting groups are removed by metallic reducing agents, for example zinc in the presence of acetic acid.
• tert.-butoxycarbonyl or the hydroxyl-protecting groups tert.-lower alkyl, e.g. tert.-butyl; substituted oxymethyl, e.g. methoxymethyl, ethoxymethyl or 1-ethoxyethyl; substituted thiomethyl, e.g. methylthiomethyl; or 2-oxacycloalkyl, e.g. 2-tetrahydropyranyl or 2-tetrahydrofuryl, are cleaved with an acid, for example a mineral acid, e.g. hydrochloric acid; an organic carboxylic acid, e.g.
• acetic acid formic acid, acetic acid or trifluoroacetic acid; an organic sulfonic acid, e.g. p-toluenesulfonic acid; or an ion exchange resin in acid form; optionally in the presence of water or an organic solvent, for example a lower alkanol, e.g. methanol; an ether, e.g. diethyl ether or tetrahydrofuran; or a chlorinated hydrocarbon, e.g. methylene chloride or chloroform.
• an organic solvent for example a lower alkanol, e.g. methanol
• an ether e.g. diethyl ether or tetrahydrofuran
• chlorinated hydrocarbon e.g. methylene chloride or chloroform.
• a silyl protecting group for example trimethylsilyl, tert.-butyldimethylsilyl or 2-trimethylsilylethoxycarbonyl, is cleaved by the mentioned acids, or preferably, by fluoride anions, for example by sodium fluoride, potassium fluoride or a quaternary ammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in a polar solvent, for example dimethylsulphoxide, dimethyl formamide or acetonitrile, optionally in the presence of a crown ether.
• the cleavage of protecting groups is usually carried out at low or ambient temperature, for example between 0 C and room temperature, e.g. around 20 C.
• the protecting groups may be cleaved in one step or consecutively, depending on the kind of protecting group present.
• the starting material of formula IX is prepared according to any of the mentioned processes (a), (b), (c) or (d), using the corresponding compounds II to VIII, respectively, wherein the residue A is replaced by A and/or B is replaced by B'.
• the corresponding protected compounds are available according to methods described in the above-mentioned standard works on protective groups in organic chemistry.
• the compounds of the invention can be converted into each other according to methods known per se.
• this nitrogen atom can be alkylated, for example methylated or benzylated, using conventional alkylating agents, for example alkyl halides or sulfonates, e.g. methyl iodide, methyl p-toluenesulfonate or benzyl bromide.
• alkylating agents for example alkyl halides or sulfonates, e.g. methyl iodide, methyl p-toluenesulfonate or benzyl bromide.
• this substituent can be converted to alkoxy by the mentioned alkylating agents.
• this substituent can be converted to hydroxy using suitable acids, for example hydroiodic acid or, preferably, boron tribromide.
• the compounds of the invention can be converted into lower alkyl enol ethers thereof according to methods known in the art.
• methyl enol ethers are formed from compounds of formula I and diazomethane, for example in etheral solution at around 0 C.
• the compounds of the invention are converted into alkali metal salts, for example sodium salts, as described further below, and the salts treated with lower alkyl halides or sulfonates, for example methyl iodide or ethyl p-toluenesulfonate, in a polar solvent at temperatures between 0 and 50 . C, for example around room temperature.
• the compounds of the invention can be converted into salts thereof by conventional means well-known in the art, for example by treatment with aqueous alkali metal or earth alkali metal hydroxide, preferably in stoichiometric amounts or with a slight excess, advantageously in the presence of an organic co-solvent, for example a lower alkanol, e.g. ethanol or methanol, or an ether, e.g. tetrahydrofuran.
• organic co-solvent for example a lower alkanol, e.g. ethanol or methanol
• ether e.g. tetrahydrofuran
• Other metal compounds can be used, for example carbonates, e.g. sodium carbonate.
• ammonium salts a stoichiometric amount or a slight excess of the corresponding organic amine in a suitable solvent, for example a lower alkanol, e.g.
• Acid addition salts of compounds of formula I are obtained in customary manner, for example by treatment with the corresponding mineral acid in an alcoholic or etheral solvent.
• Inner salts can be formed, for example, by neutralizing salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion exchangers.
• Salts can be converted in customary manner into the free compounds; metal and ammonium salts, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent. Salts can be transferred into other salts by stepwise preparing the free compound and then the other salt thereof as described above, by treating the salt with an excess of the corresponding salt-forming reagent and, if possible, crystallizing the desired salt from a suitable solvent, or by treating the salt with the corresponding ion exchange resin.
• diluents preferably such as are inert to the reagents and are solvents thereof, of catalysts, and/or of condensing or neutralization agents, and in air or under inert atmosphere, at low temperatures, room temperature or elevated temperatures, and at atmospheric or superatmospheric pressure.
• the invention also comprises any modification of the above processes, wherein a compound resulting as an intermediate at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salt or reactive derivative.
• those starting materials are advantageously selected which yield the above-described preferred embodiments of the invention.
• the invention also relates to novel intermediates and processes for their manufacture.
• the new compounds may be in the form of one isomer, tautomer or mixtures thereof, provided such are possible.
• the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for the crystallization.
• compositions according to the invention are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, for the alleviation and treatment of pain and inflammatory and arthritic diseases, such as osteoarthritis and rheumatoid arthritis, comprising an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.
• the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral, parenteral or topical application.
• Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also (c) binders, e.g.
• Injectable compositions are preferably aqueous isotonic solutions or suspensions. Suppositories or topical lotions are advantageously made from fatty emulsions or suspensions.
• compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
• the invention relates also to a method of treating inflammatory and arthritic conditions in mammals, which comprises administering to said mammals a correspondingly effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
• the dosage of the active ingredient depends on the species, body weight, age and individual condition of the warm-blooded animal, on the disease to be treated and also on the mode of administration.
• a unit dosage for a mammal of about 50 to 70 kg may contain between about 10 to 200 mg of the active ingredient.
• the starting material is prepared as follows:
• Example 2 Using essentially the procedure of Example 1, 2.1 g (0.014 mol) of ⁇ -oxo- ⁇ -(2-thienyl)propionitrile and 1.7 g (0.017 mol) of triethylamine in 50 ml of toluene, benzene or ethyl acetate are treated with 0.014 to 0.016 mol of the desired arylisocyanate. The resulting solution is let stand overnight, then evaporated, and the crude material taken up in methanol and treated with 0.1 N hydrochloric acid. The crude product is collected and purified by trituration with the appropriate indicated solvent or by dissolving in dilute NaOH solution, filtering, and reacidifying with 5 N HCI; and finally recrystallized from the appropriate indicated solvent to give the compounds listed in Table I.
• the starting material is prepared as follows:
• the starting material ⁇ -(5-bromo-2-furyl)- ⁇ -oxopropionitrile, m.p. 158-9° is essentially prepared as described for ⁇ -(2-furyl)- ⁇ -oxopropionitrile in Example 8, using 2.4 g of 50% sodium hydride, 11 g of ethyl 5-bromo-2-furoate (Ann. Chem. 232, 51) and 4.1 g of acetonitrile.
• a suspension of 4.7 g of the sodium salt of ⁇ -oxo- ⁇ -(3-pyridyl)propionitrile in 35 ml of dimethylsulfoxide is treated with 4.5 g of p-fluorophenylisocyanate. Following the mild exothermic reaction, the mixture is let stand overnight. The mixture is treated with water (ca. 400 ml) and 5 ml of 10% NaOH solution, and the solution is filtered and carefully acidified with 5 N HCI. The product is collected, washed with water, and air dried to give yellow crystals, m.p. 231-2° (dec.). The compound is recrystallized from DMF and ethanol.
• the starting material is prepared as follows:
• an aqueous solution (100 ml) of 20 g of the sodium salt of methyl 2,4-dioxovalerate is treated with a solution of 6.4 ml of methylhydrazine in aqueous sulfuric acid prepared from 12.5 g of cold cone. H 2 S0 4 and 20 g of ice. After stirring for 1 hr, the solution is carefully made alkaline with sodium hydroxide solution. The products are extracted with diethyl ether, and the etheral solution dried with sodium sulfate and evaporated.
• a solution of 13.2 g of methyl 1,5-dimethyl-3-pyrazolylcarboxylate in 20 ml of acetonitrile is added to a suspension of 6.7 g of 50% sodium hydride (washed oil-free by decantation with petroleum ether) in 25 ml of DMF.
• the reaction is initiated by warming briefly on a steam cone, with swirling. After standing overnight, the solidified mixture is treated with water, the solution filtered, and acidified to pH 6 with 5 N HCI. After chilling, the crystalline product is collected, washed with cold water, and dried. Recrystallization from ethanol gives colorless crystals of ⁇ -(1,5-dimethyl-3-pyrazolyl)- ⁇ -oxopropionitrile, m.p. 114-6°.
• a solution of 1.3 g of ⁇ -(1,5-dimethyl-3-pyrazolyl)- ⁇ -oxopropionitrile and 0.9 g of triethylamine in 30 ml of toluene is treated with 1.05 g of phenylisocyanate. After standing overnight, evaporation, and treatment with a solution of 3 ml of 5 N HCI in 250 ml of water, the crude solid is purified by dissolving in dilute NaOH solution, filtering, reacidifying with 5 N HCI to give, after collecting, washing with water and air drying, crystals, m.p. 219-221°. Recrystallization from ethanol and ethyl acetate, and treatment with Norit gives colorless crystals, m.p. 233-5 *.
• the starting material is prepared as follows:
• the starting material is prepared as follows:
• the starting material is prepared as follows:
• a sample of the sodium salt is treated with glacial acetic acid, the free imidazolyl ⁇ -ketonitrile extracted with acetone, and converted to the corresponding hydrochloride for characterization; light orange crystals from ethanol and methanol, m.p. 210-2° (dec.).
• a suspension of 4.8 g of the sodium salt of ⁇ -(1-methyl-5-imidazolyl)- ⁇ -oxopropionitrile in 25 ml of DMF is mixed with 6.6 g of p-chlorophenylisocyanate to give a brown suspension which, after standing overnight, is treated with water and 2 ml of 10% NaOH, filtered, and the filtrate neutralized with glacial acetic acid.
• the product is collected, washed with water, and dried; yellow crystals, m.p. 239-241 (dec.). Recrystallization from DMF and ethanol gives pale yellow, voluminous crystals, m.p. 245-6° (dec.).
• the starting material is prepared as follows:
• Sodium ethoxide is prepared from 2.1 g of sodium and ethanol, dried in vacuo, and suspended in 200 ml of dry toluene. To this suspension is added a solution of 13.0 g of ethyl 1-methylimidazolyl-2-carboxylate and 7 g of acetonitrile in 50 ml of toluene. The suspension is refluxed with stirring for 150 min. The red suspension is diluted with 100 ml of dry ethyl ether and the sodium salt of ⁇ -(1-methyl-2-imidazolyl- ⁇ -oxopropionitrile collected, washed with ethyl ether and dried; yellow-orange solid, m.p. 217-226 . A sample of the sodium salt is treated with glacial acetic acid, and the free ⁇ -ketonitrile triturated with ether and acetone and recrystallized from ethanol; needles, m.p. 109-111°.
• the compound is obtained by reaction of the sodium salt of ⁇ -(1-methyl-2-imidazolyl)- ⁇ -oxopropionitrile with p-fluorophenylisocyanate following the procedure of Example 22; solid, m.p. 241-2° (dec.). Recrystal- lizati ⁇ n from ethanol and DMF gives colorless crystals, m.p. 243-4° (dec.).
• the compound is obtained by reaction of the sodium salt of ⁇ -(1-methyl-2-imidazolyl)- ⁇ -oxopropionitrile with p-chlorophenylisocyanate following the procedure of Example 22; solid, m.p. 235-6° (dec.). Recrystallization from ethanol and methanol gives crystals, m.p. 238-9° (dec.).
• the starting material is prepared as follows:
• the compound is obtained by reaction of 2,4-dimethylthiazolyl-5-carbonyl chloride with a-cyano-p-fluoroacetanilide following the procedure of Example 25; solid, m.p 196-8°. Recrystallization from methanol and ethanol gives crystals, m.p. 199-200°.
• the compound is obtained by reaction of 2,4-dimethylthiazolyl-5-carbonyl chloride with p-chloro-a-cyanoacetanilide following the procedure of Example 25; solid, m.p. 203-5°. Recrystallization from ethyl acetate gives crystals, m.p 208-9°.
• the starting material is prepared as follows:
• the compound is obtained by reaction of ⁇ -oxo- ⁇ -(2-phenyl-4-thiazolyl)propionitrile with p-fluorophenylisocyanate following the procedure of Example 28. After trituration with ethanol and methanol, the product of m.p. 214-6° is collected. Recrystallization from ethyl acetate raises the m.p. to 215-6°.
• the compound is obtained by reaction of ⁇ -oxo- ⁇ -(2-phenyl-4-thiazolyl)propionitrile with p-chlorophenylisocyanate following the procedure of Example 28. After trituration with ethanol and methanol, the product of m.p. 222-5° is collected. Recrystallization from ethyl acetate raises the m.p. to 224-6°.
• the starting material is prepared as follows:
• the starting material is prepared as follows:
• capsules are prepared containing 10-200 mg of the other compounds disclosed and illustrated herein.
• All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35 *, broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches uppers bisected.
• tablets are prepared containing 10-200 mg of one of the other compounds illustrated by the previous examples.

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